US20200405822A1 - A pharmaceutical composition for anaemia - Google Patents
A pharmaceutical composition for anaemia Download PDFInfo
- Publication number
- US20200405822A1 US20200405822A1 US16/978,989 US201916978989A US2020405822A1 US 20200405822 A1 US20200405822 A1 US 20200405822A1 US 201916978989 A US201916978989 A US 201916978989A US 2020405822 A1 US2020405822 A1 US 2020405822A1
- Authority
- US
- United States
- Prior art keywords
- composition
- iron
- pharmaceutical composition
- lactoferrin
- ranges
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 130
- 208000007502 anemia Diseases 0.000 title claims abstract description 39
- 108010063045 Lactoferrin Proteins 0.000 claims abstract description 154
- CSSYQJWUGATIHM-IKGCZBKSSA-N l-phenylalanyl-l-lysyl-l-cysteinyl-l-arginyl-l-arginyl-l-tryptophyl-l-glutaminyl-l-tryptophyl-l-arginyl-l-methionyl-l-lysyl-l-lysyl-l-leucylglycyl-l-alanyl-l-prolyl-l-seryl-l-isoleucyl-l-threonyl-l-cysteinyl-l-valyl-l-arginyl-l-arginyl-l-alanyl-l-phenylal Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CSSYQJWUGATIHM-IKGCZBKSSA-N 0.000 claims abstract description 153
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Definitions
- the present invention relates to a pharmaceutical composition/formulation for use in treatment of Iron Deficiency Anaemia (IDA), Anaemia of Inflammation (AOI) and neuro-degenerative disorders. More particularly, the invention relates to a pharmaceutical composition/formulation comprising a synergistic combination of Lactoferrin (LF) and one or more natural Guanosine Nucleotide or a pharmaceutically acceptable salt thereof.
- IDA Iron Deficiency Anaemia
- AOI Anaemia of Inflammation
- LF Lactoferrin
- the invention also provides various formulations and methods of preparing the same.
- Anaemia is usually referred to a condition wherein the total amount of red blood cells or hemoglobin in the blood is decreased.
- Anaemia caused by lack of iron is known as Iron-deficiency anaemia (IDA).
- IDA Iron-deficiency anaemia
- IDA relates to a condition when the body doesn't have enough iron to produce adequate amounts of hemoglobin. In such conditions, the blood is unable to carry enough oxygen to the tissues throughout the body and circulation.
- This anaemia is usually caused by blood loss, insufficient dietary intake and/or poor absorption of iron from food itself. Instances of severe blood loss can include heavy bleeding during menstruation, during childbirth, uterine fibroids, stomach ulcers, colon cancer, and urinary tract bleeding etc. Apart from these conditions, poor absorption of iron may occur due to result of conditions such as Crohn's disease or a gastric bypass.
- obesity leads to chronic overexpression of hepcidin as a downstream effect of low-grade chronic inflammation. Specifically, obesity leads to increased interleukin (IL)-6 and IL-1 levels, which up-regulate hepcidin. Similarly, maternal obesity is associated with impaired iron transfer to the foetus. This is due to the effects of a chronic pro-inflammatory environment and increased levels of hepcidin.
- IL-6 and IL-1 interleukin-1
- hypoferremia and IDA represent a risk factor for maternal and infant health.
- hypoferremia and IDA in pregnancy is highly prevalent due to increased iron requirement, enhanced blood volume, and development of the fetal-placenta unit (see, e.g., Umbreit, Am. J. Hematol. 78:225-31 (2005); School, Am. J. Clin. Nutr. 81: 1218-22 (2005)).
- pregnancy-associated anemia results in preterm delivery, retardation of fetal growth, low birth weight, and inferior neonatal health. It is estimated that 41.8% of pregnant women worldwide are anaemic and at least half of this anaemia burden is assumed to be due to iron deficiency.
- Iron recycling is primarily performed by reticuo-endothelial macrophages which phagocytize senescent RBCs and then export iron via ferroportin (FPN) back into the circulating pool of Tf-bound iron. Excess iron is also stored within hepatocytes. Hepcidin regulates systemic iron balance by inducing ferroportin degradation to inhibit iron absorption from the duodenum and iron release from macrophage and hepatocyte stores.
- FPN ferroportin
- Iron homeostasis is tightly regulated through iron absorption, storage and transport. Iron absorption occurs in the proximal duodenum and includes in the apical site of enterocytes the reduction of ferric ions by a ferrireductase (duodenal cytochrome B, DCYTB), the apical uptake and the trans-cellular trafficking via divalent metal transporter 1 (DMT1), the storage into ferritin and finally, the basolateral efflux by the iron transporter ferroportin.
- a ferrireductase dueodenal cytochrome B, DCYTB
- DMT1 divalent metal transporter 1
- Ferroportin the only known cellular iron exporter from tissues into blood, has been found in all cell types involved in iron export, including enterocytes, hepatocytes, placental cells and macrophages which recycle 20 mg of iron daily from lysed erythrocytes for erythropoiesis.
- hepcidin a circulating peptide hormone synthesized by hepatocytes in iron loading conditions and secreted in plasma and urine.
- Hepcidin regulates the entry of iron into plasma through ferroportin. Binding of hepcidin with ferroportin causes the formation of a hepcidin-ferroportin complex resulting in ferroportin phosphorylation, internalization and degradation in lysosomes. Consequently, iron export is hindered and cytosolic iron storage in ferritin is enhanced.
- Iron homeostasis disorders appear to arise from hepcidin and/or ferroportin dysregulation. It is well known that iron loading and Interleukin-6 (II-6) increase hepcidin gene transcription in hepatocytes.
- II-6 Interleukin-6
- ACD/AOI chronic disease/Inflammation
- CKD chronic kidney disease
- EPO erythropoietin
- Hepcidin level also increases along with the CKD regardless of the inflammatory state. Hemochromatosis can be characterized by low hepcidin production, which increases intestinal absorption of iron and iron release by macrophages which inevitably leads to progressive iron storage in tissues. In chronic diseases, high hepcidin production inhibits iron release from macrophages and intestinal absorption of iron which consequently induces an anaemic condition.
- Oral Iron supplements are available commercially either in rapid release dosage forms and/or in controlled release dosage forms.
- Rapid release iron supplement dosage forms typically contain a “rapidly dissolving” iron salt which are significantly more soluble in water and gastrointestinal fluids than other salts and metallic forms of iron.
- Administration of rapid release iron supplement dosage forms can cause excessively high maximum (max) blood-iron concentrations (C), i.e., C max , within a short period of time (T) between administration and attainment of C max , i.e., T max .
- C max blood-iron concentrations
- T max short period of time
- rapid release iron supplement formulations can cause unpleasant, harmful, or even fatal side effects. Such side effects may include stomach irritation, constipation, and iron poisoning.
- iron supplements from the gastrointestinal tract is reduced in the presence of divalent non-iron mineral supplements such as magnesium and calcium.
- divalent non-iron mineral supplements such as magnesium and calcium.
- the administration of a high dose of poorly absorbed iron complexes may cause siderosis of the gut wall and a variety of side effects such as nausea, vomiting, constipation, diarrhoea, abdominal discomfort, shortness of breath, weight loss, headaches, dizziness, anorexia, fatigue, darkened urine, heartburn, darkened teeth, darkened stool, and heavy malodorous stools.
- Controlled release iron supplement dosage forms were developed in an attempt to reduce side effects such as those noted above, commonly associated with known iron supplementation therapies.
- Controlled release iron supplement dosage forms commonly use an iron (II) salt encapsulated in or mixed with a release rate modifying matrix, an iron (III) salt, carbonyl iron or other metallic iron of naturally poor solubility, crystalline iron oxide, iron salt or carbonyl iron complexes with a release rate modifying protein, amino acid, organic acid, natural polymer, anionic complexing agent or synthetic polymer.
- Iron supplements designed to provide “sustained delivery” of iron have been associated with unpleasant tastes and odors, nausea, stomach irritation and gas formation.
- Parenteral iron is required for those not tolerating oral iron or who need rapid correction of anaemia (severe anaemia in last month of pregnancy) and where oral therapy has failed.
- Parenteral iron can be administered intramuscular (IM) or intravenous (IV).
- IM intramuscular
- IV intravenous
- the main drawbacks of IM route are pain, staining of skin, myalgia, arthralgia and injection abscess.
- Intravenous iron can be administered as total dose infusion; however, utmost caution is needed as anaphylaxis can occur.
- Iron dextran and iron polymaltose preparations can be used by both IM and IV routes. Two newer IV preparations—iron sucrose and ferric gluconate are associated with reduced side-effects. However, it is a costly alternative and is not necessarily favored by all patients.
- hepcidin levels increased in response to iron therapy regardless of administering oral iron supplement for long term therapy. This increased level of hepcidin is directly associated with decreased iron absorption of subsequent daily iron doses or twice-daily iron doses.
- the traditional treatments i.e. oral iron therapy and blood transfusion involve significant drawbacks. Oral iron is frequently restricted by limited absorption, low tolerability, non-compliance and side effects.
- I.V. iron could promote cytotoxicity and tissue injury; exacerbate oxidative stress and thus endothelial dysfunction, as well as inflammation and the progression of both CKD and cardiovascular disease. Therefore, it is necessary to regulate hepcidin level which would maintain Iron Homeostasis which in no manner can be achieved by Oral or I.V. Iron Supplement.
- Lactoferrin also known as lactotransferrin (LTF)
- LTF lactotransferrin
- LF is a multifunctional protein of the transferrin family.
- LF is a globular glycoprotein with a molecular mass of about 80 kDa widely represented in various secretory fluids, such as milk, saliva, tears, and nasal secretions. It is also present in the milk of humans and other mammals, in the blood plasma and neutrophils and is one of the major proteins of virtually all exocrine secretions of mammals.
- LF can be purified from milk or produced recombinantly.
- Human colostrum (“first milk”) has the highest concentration (7 g/L); followed by human milk (1 g/L), then cow milk (150 mg/L).
- LF is one of the transferrin proteins that transfer iron to the cells and control the level of free iron in the blood and external secretions.
- LF belongs to the innate immune system and apart from its main biological function, namely binding and transport of iron ions. It is also known to have antibacterial, antiviral, anti-parasitic, catalytic, anti-cancer, and anti-allergic functions and properties.
- LF has been demonstrated to reduce both IL-6 levels and independently reduce hepcidin gene expression. Its antibacterial properties have also been demonstrated to down-regulate the over-expression of macrophages resulting into reduced inflammation and up-regulation of ferroportin expression. Moreover, compared to oral iron supplements, administration of LF has also shown to demonstrate no or minimal side effects such as gastrointestinal irritation, nausea, vomiting, constipation, darkened urine, darkened stool, etc.
- Lactoferrin is present in either iron-free (i.e., apo-type) or iron-saturated state (i.e., holo-type) depending on whether it binds irons, which in turn determines the biological properties of lactoferrin.
- the apo-type lactoferrin is present in normal human milk.
- Bovine lactoferrin is bovine milk extracted from the form of a basic protein having a variety of biologically active components to develop the protein value.
- iron plays an essential role in maintaining various biological functions in all living organisms. Iron affects synthesis and signalling of the neurotransmitters dopamine, noradrenalin, adrenaline and 5-hydroxytryptamine, which are involved in emotion, attention, reward, movement and various other functions.
- a new approach to manage neuro-degenerative disorders can be achieved by iron homeostasis.
- the present therapies mainly serve as a band-aid therapy, rather than working on the major cause of such neurodegenerative disease which is dysregulation of iron homeostasis. Reduction in IL-6 levels and reduction in Hepcidin gene expression are the two important aspects that are responsible for iron movement in and out of the cells. Thus there is a need to develop formulations for maintaining iron homeostasis by hepcidin regulation and hence provide a natural treatment for the neuro degenerative disorder.
- Nucleotides are small molecules composed of three parts, a nitrogenous base, a sugar and one or more phosphates. Nucleotides play many roles in cells. They are the precursors for the nucleic acids. ATP, a nucleotide, is the primary energy currency in a cell. Nucleotides are also used as regulatory molecules. Guanosine is a purine nucleoside comprising guanine attached to ribofuranose, a ribose ring via a ⁇ -N-glycosidic bond. Guanosine after phosphorylation turns in to Guanosine monophosphate (GIP), Guanosine diphosphate (GDP), and Guanosine triphosphate (GTP).
- GIP Guanosine monophosphate
- GDP Guanosine diphosphate
- GTP Guanosine triphosphate
- GMP also known as 5′-guanidylic acid or guanylic acid (conjugate base guanylate)
- guanylic acid conjuggate base guanylate
- GMP is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid with the nucleoside guanosine. It consists of the phosphate group, the pentose sugar ribose, and the nucleobase guanine and hence it is a ribonucleoside monophosphate.
- GMP is commercially produced by microbial fermentation.
- GDP is a nucleoside diphosphate which is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of a pyrophosphate group, a pentose sugar ribose and the nucleobase guanine.
- GTP is a purine nucleoside triphosphate which is one of the important blocks required for the synthesis of RNA during the transcription. It has also the role of a source of energy as an activator of substrates in metabolic reactions and used as a source of energy for protein synthesis and gluconeogenesis.
- a Stable binding with hepcidin, preventing hepcidin induced FPN internalization with effective cellular iron efflux.
- b Increased expression of DMT1 and TFR1 (Transferrin receptor) indicating effective iron distribution and decreased ferritin level in the enterocyte, thus preventing increased iron absorption in the cells.
- c Stabilization of Ferroportin in itself resulting in higher effectiveness of iron efflux.
- WO 2011/019641 A2 discloses Nutritional compositions and methods of making and using the nutritional compositions wherein the said nutritional compositions comprise one or more exogenous nucleotides selected from the group consisting of 5′-Adenosine Monophosphate, 5′-Guanosine Monophosphate, 5′-Cytosine Monophosphate, 5′-Uracil Monophosphate, 5′-Inosine Monophosphate or 5′-Thymine Monophosphate.
- the nutritional compositions further comprise at least one prebiotic, at least one probiotic, at least one symbiotic, at least one amino acid, at least one fish oil; at least one phytonutrient; at least one antioxidant; at least one transforming growth factor-beta; or Lactoferrin; or combinations thereof.
- the said nutritional composition can be in an administrable form such as pharmaceutical formulations, nutritional formulations, dietary supplements, functional foods, beverage products or a combination thereof.
- the nutritional composition can include the exogenous nucleotides in an amount to be administered ranging from about 0.1 mg/day to about 5.0-6.0 grams/day, including all number, whole or fractions.
- WO 2018/009647 A1 discloses a nutritional formula in the form of powder or liquid comprising alpha-lactalbumin enriched whey protein concentrate; beta-casein enriched milk protein; mildly hydrolyzed milk protein; osteopontin; lactoferrin; oleic acid-palmitic acid-oleic acid triglyceride, wherein palmitic acid is at the SN-2 position of the glycerol backbone of the triglyceride; lactose, wherein the lactose is reduced lactose; lutein; docosahexanoic acid; arachidonic acid; galactooligosaccharides; and polydextrose.
- the nutritional formula of the said invention provides a subject with nutrients similar to those provided by human breast milk.
- US 2002/0022052 A1 discloses substantially water free compositions for transdermal or trans epithelial delivery comprising at least one biologically active agent and a pharmaceutically acceptable carrier wherein the biologically active agent is induced into the skin by massage and includes a plurality of fine solid particles sized less than 2 microns dispersed through said carrier. Further, the compositions covered in the said application are in the form of ointment or cream.
- WO2007022537A2 discloses the method of treating a disease or condition, such as Anaemia, by administering a chemotactic modulator composition wherein the chemotactic modulator can be selected from the group consisting of Lactoferrin or cGMP.
- the composition can be administered topically, orally or parenterally and can be in the form of topical gel, a solution, or a tablet.
- a formulation which supports nutritional requirement along with maintaining iron homeostasis.
- composition/formulation comprising natural ingredients which will reduce ferritin bind iron stores, increase iron efflux in systemic circulation, improve Ferroportin stabilization, decreased Hepcidin and IL-6 levels, reduce inflammatory pathways further affecting hepcidin-Fpn balance and also act as a natural treatment to iron deficiency anaemia (IDA) and anaemia of inflammation (AOI) without any side effects of iron administration by maintaining perfect iron homeostasis with hepcidin regulation.
- IDA iron deficiency anaemia
- AOI anaemia of inflammation
- the present application provides a pharmaceutical composition/formulation for use in treatment of Iron Deficiency Anaemia (IDA) and Anaemia of Inflammation (AOI).
- IDA Iron Deficiency Anaemia
- AOI Anaemia of Inflammation
- the pharmaceutical composition/formulation of the present invention can also be used in the treatment for Neuro-Degenerative Disorders.
- the Lactoferrin combination of the present invention is able to provide a safe pharmaceutical composition/formulation with enhanced and/or synergistic effects compared to Lactoferrin alone in the treatment or prevention of IDA or AOI.
- the present application provides a pharmaceutical composition/formulation comprising a synergistic combination of Lactoferrin and one or more natural Guanosine Nucleotide or a pharmaceutically acceptable salt thereof.
- the present invention provides a pharmaceutical composition/formulation for use in treatment of IDA and AOI, wherein said composition/formulation comprises a synergistic combination of Lactoferrin, one or more natural Guanosine Nucleotide or a pharmaceutically acceptable salt thereof along with pharmaceutically acceptable excipient(s).
- the pharmaceutical composition/formulation of the present invention additionally comprises elemental iron, vitamin C (ascorbic acid), vitamin A (beta carotene), folic acid, folate, vitamin B or a combination thereof.
- composition/formulation a process for the preparation of composition/formulation.
- the process for preparation of the composition comprises:
- the process further comprises preparing the seal coating and enteric coating solution for enteric coated tablets, film coating solution for film coated tablets and filling and scaling for the capsule dosage forms.
- composition of this invention is formulated as a composition for an oral formulation and is made into an enteric-coated dosage form.
- Lactoferrin breaks down into several large fragments by the gastric digestive enzyme, pepsin, but in case of direct intra-duodenal administration it may reach intestine and exist there for a few hours. However, only the intact native Lactoferrin may reach the gut-associated lymphoid tissue (GALT) and enter the lymphatic system, which is necessary for efficacy. The bioavailability of Lactoferrin is limited as it is susceptible to digestive enzymes in gastrointestinal tract. In this regard, there is a high demand for an appropriate Lactoferrin delivery system that should protect Lactoferrin from digestion in stomach and facilitate its permeability across intestinal epithelium.
- GALT gut-associated lymphoid tissue
- the composition containing Lactoferrin which acts on the mucosa of the intestinal tract and is highly sensitive to pepsin, it is technologically meaningful to make the composition into an enteric-coated dosage form.
- an enteric coated LF tablet has been developed for the delivery of an intact molecule of the LF onto the receptor in the intestine.
- LF molecules are protected from the proteolytic digestion in the stomach as the tablet is coated by an acid-resistant material, which dissolves easily in a neutral pH condition in the intestine.
- the enteric-coated LF also known to improve visceral fat-type obesity related for the metabolic syndrome in some studies.
- the formulations of the present invention are coated with enteric coated material, which dissolves easily under the neutral pH conditions in the intestine and provide desired pharmacological action.
- FIG. 1 Effect of test composition/formulation on Hemoglobin level compared to disease control.
- FIG. 2 Effect of test composition/formulation on Hematocrit % level compared to disease control.
- FIG. 3 Effect of test composition/formulation on serum iron level compared to disease control.
- FIG. 4 Effect of test composition/formulation on Ferroportin level compared to disease control.
- FIG. 5 Effect of test composition/formulation on Ferritin level compared to disease control.
- FIG. 6 Effect of test composition/formulation on Hepcidin level compared to disease control.
- FIG. 7 Effect of test composition/formulation on IL-6 level compared to disease control.
- the present invention is directed to a pharmaceutical composition/formulation comprising a synergistic combination of Lactoferrin and one or more natural Guanosine Nucleotide or a pharmaceutically acceptable salt thereof for treatment of Iron Deficiency Anaemia (IDA) and Anaemia of inflammation (AOI).
- IDA Iron Deficiency Anaemia
- AOI Anaemia of inflammation
- the inventors carried out an extensive research studies along with pre-clinical studies and found that the combination of Lactoferrin and one or more natural Guanosine Nucleotide or a pharmaceutically acceptable salt thereof provides synergistic effect for treatment of IDA and AOL.
- the pharmaceutical composition/formulation of the present invention can also be used in the treatment for Neuro-Degenerative Disorders.
- An objective of the present invention is to provide a pharmaceutical composition/formulation comprising a synergistic combination of Lactoferrin and one or more natural Guanosine Nucleotide or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition/formulation of the present invention may optionally comprise elemental iron, vitamin C, vitamin A, folic acid, folate, vitamin B or a combination thereof.
- the Lactoferrin combination of the present invention is able to provide a safe pharmaceutical composition/formulation of Lactoferrin with one or more natural Guanosine Nucleotide or a pharmaceutically acceptable salt thereof with enhanced and/or synergistic effects compared to Lactoferrin alone in the treatment or prevention of IDA or AOL
- the ratio of Lactoferrin:Natural Guanosine Nucleotide(s) or a pharmaceutically acceptable salt thereof is in a range of 9.1-98.7:1.3-90.9.
- the ratio of Lactoferrin:natural Guanosine Nucleotide or a pharmaceutically acceptable salt thereof is 90.91:9.09.
- Another objective of the present invention is to provide a synergistic combination of Lactoferrin along with natural Guanosine Nucleotide or a pharmaceutically acceptable salt thereof and optionally including active ingredients selected from elemental iron, vitamin C, vitamin A, folic acid, folate, vitamin B or a combination thereof.
- the pharmaceutical composition/formulation of the present invention helps to increase Hemoglobin, Hematocrit % (HCT %) and serum Iron level.
- the pharmaceutical composition/formulation of the present invention also helps to reduce Serum Ferritin, Hepcidin and IL-6 level and improve ferroportin stabilization. This hepcidin regulation leads to reduce ferritin bind iron stores, increase iron efflux in systemic circulation and improve Ferroportin stabilization.
- the pharmaceutical composition/formulation of the present invention helps to maintain iron homeostasis in the condition of IDA and AOI without any side effects.
- the pharmaceutical composition/formulation of the present invention comprises Lactoferrin, wherein the amount of Lactoferrin ranges from 5% by wt. to 90% by wt. of the composition/formulation. In an embodiment, the amount of Lactoferrin ranges from 10 to 90% by wt. In another embodiment, the amount of Lactoferrin ranges from 20 to 90% by wt. In yet another embodiment, the amount of Lactoferrin ranges from 30 to 90% by wt. In further embodiment, the amount of Lactoferrin ranges from 40 to 90% by wt. In yet another embodiment, the amount of Lactoferrin ranges from 50 to 90% by wt.
- the amount of Lactoferrin ranges from 60 to 90% by wt. In yet another embodiment, the amount of Lactoferrin ranges from 70 to 90% by wt. In further embodiment, the amount of Lactoferrin ranges from 80 to 90% by wt.
- the pharmaceutical composition/formulation of the present invention comprises Lactoferrin, wherein the amount of Lactoferrin in the composition/formulation ranges from 25 mg to 750 mg per unit dose.
- Lactoferrin is present in either iron-free (i.e., apo-type) or partially saturated iron (i.e., native or bovine) or iron-saturated state (i.e., holo-type) depending on whether it binds irons, which in turn determines the biological properties of Lactoferrin.
- the pharmaceutical composition/formulation of the present invention further comprises at least one natural Guanosine Nucleotides or a pharmaceutically acceptable salt thereof wherein the natural Guanosine Nucleotides are selected from GMP, GDP, GTP or the like.
- the amount of Guanosine Nucleotides or a pharmaceutically acceptable salt thereof that can be used in the composition/formulation of the present invention ranges from 1.0% by wt. to 75% by wt. of the composition/formulation. In an embodiment, the amount of Guanosine Nucleotides or a pharmaceutically acceptable salt thereof ranges from 5 to 75% by wt.
- the amount of Guanosine Nucleotides or a pharmaceutically acceptable salt thereof ranges from 10 to 75% by wt. In further embodiment, the amount of Guanosine Nucleotides or a pharmaceutically acceptable salt thereof ranges from 20 to 75% by wt. In yet another embodiment, the amount of Guanosine Nucleotides or a pharmaceutically acceptable salt thereof ranges from 30 to 75% by wt. In further embodiment, the amount of Guanosine Nucleotides or a pharmaceutically acceptable salt thereof ranges from 40 to 75% by wt. In yet another embodiment, the amount of Guanosine Nucleotides or a pharmaceutically acceptable salt thereof ranges from 50 to 75% by wt.
- the amount of Guanosine Nucleotides or a pharmaceutically acceptable salt thereof ranges from 60 to 75% by wt. In yet another embodiment, the amount of Guanosine Nucleotides or a pharmaceutically acceptable salt thereof ranges from 70 to 75% by wt.
- the amount of Guanosine Nucleotides or a pharmaceutically acceptable salt thereof that can be used in the pharmaceutical composition/formulation of the present invention ranges from 0.25 mg to 1000 mg per unit dose.
- a pharmaceutically acceptable salt suitable for the invention may be selected from a hydrochloride, a sulfate, a phosphate, acetate, lactate, citrate, a pantothenate, an ascorbate, a succinate, maleate, fumarate, gluconate, a magnesium salt, potassium, sodium, zinc, and the salts of diethanolamine or a combination thereof.
- the pharmaceutical composition/formulation of the present invention comprises a synergistic combination of Lactoferrin, Disodium GMP and pharmaceutically acceptable excipients.
- the pharmaceutical composition/formulation of the present invention optionally comprises other active ingredients such as Iron.
- The, pharmaceutical composition/formulation of the present invention may include iron as physiologically acceptable grades of elemental iron that can be used in a single dosage form composition of the disclosure and include without limitation elemental iron, iron compounds in the form of a salt (soluble, slightly soluble, or insoluble), chelated iron (specifically, chelated to an amino acid), iron complexes, non-reactive iron such as carbonyl iron and reduced iron, and combinations thereof.
- Non-limiting examples of suitable soluble iron salts include ferric hypophosphite, ferric albuminate, ferric chloride, ferric citrate, ferric oxide saccharate, ferric ammonium citrate, ferrous chloride, ferrous gluconate, ferrous iodide, ferrous sulfate, ferrous lactate, ferrous fumarate, heme, ferric trisglycinate, ferrous bisglycinate, ferrous asparto glycinate, ferric nitrate, ferrous hydroxide saccharate, ferric sulfate, ferric gluconate, ferric aspartate, ferrous sulfate heptahydrate, ferrous phosphate, ferric ascorbate, ferrous formate, ferrous acetate, ferrous malate, ferrous glutamate, ferroglycine sulfate, ferric oxide hydrate, ferric pyrophosphate soluble, ferric hydroxide saccharate, ferric manganese saccharate, ferric
- Non-limiting examples of suitable slightly soluble iron salts include ferric acetate, ferric fluoride, ferric phosphate, ferric pyrophosphate, ferrous pyrophosphate, ferrous carbonate saccharated, ferrous carbonate mass, ferrous succinate, ferrous citrate, ferrous tartrate, ferric fumarate, ferric succinate, ferrous hydroxide, ferrous nitrate, ferrous carbonate, ferric sodium pyrophosphate, ferric tartrate, ferric potassium tartrate, ferric subcarbonate, ferric glycerophosphate, ferric saccharate, ferric hydroxide saccharate, ferric manganese saccharate, ferrous ammonium sulfate, other pharmaceutically acceptable iron salts, and combinations thereof.
- Non-limiting examples of suitable insoluble iron salts include ferric sodium pyrophosphate, ferrous carbonate, ferric hydroxide, ferrous oxide, ferric oxyhydroxide, ferrous oxalate, other pharmaceutically acceptable iron salts and combinations thereof.
- iron may be included in the form of ferrous bisglycinate or other salt form. In another specific embodiment, iron may be included in the form of ferric pyrophosphate.
- the amount of Elemental Iron that can be used in the pharmaceutical composition/formulation of the present invention ranges from 30% by wt. to 45% by wt. of the composition/formulation.
- the amount of Elemental Iron that can be used in the pharmaceutical composition/formulation of the present invention ranges from 30 mg to 500 mg per unit dose.
- the pharmaceutical composition/formulation of the present invention comprises a synergistic combination of Lactoferrin, Guanosine Nucleotides or a pharmaceutically acceptable salt thereof, Elemental Iron and pharmaceutically acceptable excipients.
- the pharmaceutical composition/formulation of the present invention comprises a synergistic combination of Lactoferrin, Disodium GMP, Ferrous bis-glycinate and pharmaceutically acceptable excipients.
- the pharmaceutical composition/formulation of the present invention optionally comprise other natural active ingredients such as Vitamin C (Ascorbic Acid), Vitamin A (Beta carotene), and Folic Acid, Folate, Vitamin B (Vitamin B 12 /Cobalamin) or the like.
- the amount of Vitamin C that can be used in the pharmaceutical composition/formulation of the present invention ranges from 5% by wt. to 65% by wt. of the composition/formulation.
- the amount of Vitamin C that can be used in the pharmaceutical composition/formulation of the present invention ranges from 20 mg to 4000 mg per unit dose.
- the pharmaceutical composition/formulation of the present invention comprises a synergistic combination of Lactoferrin, Guanosine Nucleotides or a pharmaceutically acceptable salt thereof, Vitamins and pharmaceutically acceptable excipients.
- the pharmaceutical composition/formulation of the present invention comprises a synergistic combination of Lactoferrin, Disodium GMP, vitamin C and pharmaceutically acceptable excipients.
- the amount of Vitamin A that can be used in the pharmaceutical composition/formulation of the present invention ranges from 0.5% by wt. to 3% by wt. of the composition/formulation.
- the amount of Vitamin A that can be used in the pharmaceutical composition/formulation of the present invention ranges from 450 meg to 10,000 mcg per unit dose.
- the amount of Folic Acid or Folate that can be used in the pharmaceutical composition/formulation of the present invention ranges from 0.05% by wt. to 0.75% by wt. of the composition/formulation.
- the amount of Folic Acid or Folate that can be used in the pharmaceutical composition/formulation of the present invention ranges from 6 meg to 5000 meg per unit dose.
- the pharmaceutical composition/formulation of the present invention comprises a synergistic combination of Lactoferrin, Guanosine Nucleotides or a pharmaceutically acceptable salt thereof, Elemental Iron, folic acid and pharmaceutically acceptable excipients.
- the pharmaceutical composition/formulation of the present invention comprises a synergistic combination of Lactoferrin, Disodium GMP, Ferrous bis-glycinate, folic acid and pharmaceutically acceptable excipients.
- the amount of Vitamin B (Vitamin B 12 /Cobalamin) that can be used in the pharmaceutical composition/formulation of the present invention ranges from 1% by wt. to 5% by wt. of the composition/formulation.
- the amount of Vitamin B (Vitamin B 12 /Cobalamin) that can be used in the pharmaceutical composition/formulation of the present invention ranges from 50 meg to 5000 meg per unit dose.
- the pharmaceutical composition/formulation according to the present invention can be formulated for oral administration.
- the solid compositions can be, for example, in the form of tablets, capsules, pills, hard capsules filled with liquids or solids, soft capsules, powders, granules, sachets, enteric coated tablet or capsule, modified release tablet or capsule etc.
- the pharmaceutical composition/formulation may further comprise pharmaceutically acceptable excipients.
- the preferred excipients are selected from diluent, binder, disintegrant, lubricant, glidant, etc. and combinations thereof.
- the diluents are selected from microcrystalline cellulose, lactose (anhydrous/monohydrate/spray dried), starch, cellulose powder, silicified microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium lactate, dibasic calcium phosphate (anhydrous/dibasic dehydrate/tribasic), calcium silicate, calcium sulfate, cellulose acetate, compressible sugar, confectioner's sugar, corn starch, pregelatinized starch, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, isomalt, kaolin, lactitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, medium-chain triglycerides, polydextrose, polymethacrylates, simethicone, sodium alginate, sodium chloride, sorbi
- the binder is selected from Hypromellose, starch, acacia, agar, alginic acid, calcium carbonate, calcium lactate, carbomers, carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, copovidone, corn starch, pregelatinized starch, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydrogenated vegetable oil type I, hydroxyethyl cellulose, hydroxy-ethylmethyl cellulose, hydroxypropyl cellulose, inulin, lactose, liquid glucose, low-substituted Hypromellose, magnesium aluminum silicate, maltodextrin, maltose, methyl-cellulose, microcrystalline cellulose, pectin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, povidone, sodium alg
- the disintegrating agent is selected from croscarmellose sodium, crospovidone, carboxymethyl cellulose (sodium/calcium), sodium starch glycolate, alginic acid, calcium alginate, cellulose, powdered, chitosan, colloidal silicon dioxide, corn starch, docusate sodium, glycine, guar gum, hydroxypropyl cellulose low-substituted, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, povidone, sodium alginate, pregelatinized starch or the like.
- the amount of disintegrating agent in the pharmaceutical composition/Formulation of the present invention ranges from 1% to 25% by wt. of the composition/formulation.
- the lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type I, light mineral oil, magnesium lauryl sulfate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, tale, potassium benzoate or the like.
- the amount of Lubricant in the pharmaceutical composition/formulation of the present invention ranges from 0.5% to 5% by wt. of the composition/formulation.
- the glidant is selected from colloidal silicon dioxide, tale, calcium phosphate tribasic, cellulose powdered, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, silicon dioxide or the like.
- the amount of Glidant in the pharmaceutical composition/formulation of the present invention ranges from 0.5% to 5% by wt. of the composition/formulation.
- the coating layer for the composition/formulation of the present invention is selected from film coating, seal coating or enteric coating.
- the total amount of coating agent in the pharmaceutical composition/formulation of the present invention ranges from 1.0% to 15% by wt. of the composition/formulation.
- the seal coating agent is selected from Instamoistshield (Hydroxypropyl methyl cellulose, Polyethylene glycol, Talc, Titanium dioxide, Ethyl cellulose), gelatin, copovidone, hydroxyethyl cellulose, ethyl cellulose, starch, vanillin, hydroxypropyl cellulose, guar gum, maleic acid, Hypromellose, polymethacrylates, Methyl cellulose or the like.
- the amount of seal coating agent in the pharmaceutical composition/formulation of the present invention ranges from 1.0% to 3.0% by wt. of the composition/formulation.
- the enteric coating agent is selected from Instacoat EN HPMC P (Hydroxypropyl methyl cellulose Phthalate. Polyethylene glycol, Titanium dioxide, Red Iron oxide), Methacrylate copolymer, shellac, sodium alginate, acetyltributyl citrate, carbomers, cellulose acetate phthalate, guar gum, hypromellose acetate succinate, hypromellose phthalate, polymethacrylates, polyvinyl acetate phthalate, potassium chloride, glycerin, Sureteric, tributyl citrate, triethyl citrate, triolein, white wax, zein, cellulose acetate phthalate with ethyl cellulose, chitosan, hydroxypropyl cellulose, polymethacrylates or the like.
- the amount of enteric coating agent in the pharmaceutical composition/formulation of the present invention ranges from 5.0% to 10.0% by wt. of the composition/formulation.
- the film coating agent is selected from Instacoat Universal (Hydroxypropyl methyl cellulose, Polyethylene glycol, Tale, Titanium dioxide), guar gum, Hypromellose, Povidone, hydroxypropyl cellulose, cellulose acetate, polydextrose, Ethyl cellulose, methylcellulose, gelatin, glycerin, maltodextrin, starch or the like.
- the amount of film coating agent in the pharmaceutical composition/formulation of the present invention ranges from 2.0% to 3.0% by wt. of the composition/formulation.
- the solvent is selected from water, alcohol, isopropyl alcohol, propylene glycol, almond oil, benzyl alcohol, benzyl benzoate, butylene glycol, carbon dioxide, castor oil, corn oil (maize), cottonseed oil, dibutyl phthalate, diethyl phthalate, dimethyl ether, albumin, dimethyl phthalate, dimethyl sulfoxide, dimethylacetamide, ethyl acetate, ethyl lactate, ethyl oleate, glycerin, glycofurol, isopropyl myristate, isopropyl palmitate, light mineral oil, medium-chain triglycerides, methyl lactate, mineral oil, monoethanolamine, octyldodecanol, olive oil, peanut oil, polyethylene glycol, polyoxyl 35 castor oil, propylene carbonate, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, tri
- the present invention provides a pharmaceutical composition/formulation for use in treatment of IDA and AOI, wherein said composition/formulation comprises a synergistic combination of Lactoferrin, natural Guanosine Nucleotide(s) or a pharmaceutically acceptable salt thereof, and optional active ingredients along with pharmaceutically acceptable excipient(s).
- natural Guanosine Nucleotide(s) employed in the present invention may be used in the form of their pharmaceutically acceptable salts, and also may be used alone or in appropriate association, as well as in combination with other pharmaceutically active compounds.
- compositions/formulations of the present invention are described below:
- Composition/Formulation 1 S. No Ingredients % w/w 1 Lactoferrin 5 to 90 2 Guanosine Nucleotide(s) or a pharmaceutically 1 to 75 acceptable salt thereof
- composition/Formulation 2 S. No Ingredients % w/w 1 Lactoferrin 5 to 90 2 Guanosine Nucleotide(s) or a pharmaceutically 1 to 75 acceptable salt thereof Optional ingredient 3 Vitamin A 0.5 to 3
- composition/Formulation 3 S. No Ingredients % w/w 1 Lactoferrin 5 to 90 2 Guanosine Nucleotide(s) or a pharmaceutically 1 to 75 acceptable salt thereof Optional ingredient 3 Vitamin B 1 to 5
- composition/Formulation 4 S. No Ingredients % w/w 1 Lactoferrin 5 to 90 2 Guanosine Nucleotide(s) or a pharmaceutically 1 to 75 acceptable salt thereof Optional ingredient 3 Vitamin C 5 to 65
- Composition/Formulation 5 No Ingredients % w/w 1 Lactoferrin 5 to 90 2 Guanosine Nucleotide(s) or a pharmaceutically 1 to 75 acceptable salt thereof Optional ingredient 3 Folic Acid, Folate 0.05 to 0.75
- Composition/Formulation 6 S. No Ingredients % w/w 1 Lactoferrin 5 to 90 2 Guanosine Nucleotide(s) or a pharmaceutically 1 to 75 acceptable salt thereof Optional ingredients 3 Elemental Iron 30 to 45 (Ferrous Bisglycinate, Ferric pyrophosphate, Ferrous Fumarate, Ferric citrate, etc.)
- Composition/Formulation 7 S No Ingredients % w/w 1 Lactoferrin 5 to 90 2 Guanosine Nucleotide(s) or a pharmaceutically 1 to 75 acceptable salt thereof Optional ingredients 3 Elemental Iron 30 to 45 (Ferrous Bisglycinate, Ferric pyrophosphate, Ferrous Fumarate, Ferric citrate, etc.) 4 Vitamin C 5 to 65 5 Vitamin A 0.5 to 3 6 Folic Acid, Folate 0.05 to 0.75 7 Vitamin B 1 to 5
- the uncoated tablet used as a core for enteric coated formulation in the present invention can be prepared by dry or wet granulation.
- Lactoferrin was obtained from Tatura Milk Industries Limited, 238-240 Hogan Street Tatura 3616 Vic Australia and it's trader in India Vasta Biotech Pvt. Ltd., SVN House, 10 C.P. Ramaswamy Aiyar Road, Alwarpet, India Vasta Biotech Pvt. Ltd., SVN House, 10 C.P. Ramaswamy Aiyar Road, Alwarpet, India 60 018 and guanosine nucleotides—Disodium GMP, GDP & GTP from Cima Science Wuxi Cima Science Co. Ltd, 3#Building, No. 288 Shibawan Road Wuxi 214064 Jiangsu China.
- Example 26 Stability Data & Dissolution Data of Example 1 at 40° C., 75% RH
- Example 27 Stability Data & Dissolution Data of Example 4 at 40° C., 75% RH
- Example 28 Stability Data & Dissolution Data of Example 5 at 40° C., 75% RH
- Example 29 Stability Data & Dissolution Data of Example 7 at 40° C., 75% RH
- Example 30 Stability Data & Dissolution Data or Example 9 at 40° C., 75% RH
- Example 31 Stability Data & Dissolution Data of Example 14 at 40° C., 75% RH
- Example 32 Stability Data & Dissolution Data of Example 17 at 40° C., 75% RH
- Example 33 Stability Data & Dissolution Data of Example 20 at 40° C., 75% RH
- Example 34 Stability Data & Dissolution Data of Example 22 at 40° C., 75% RH
- Example 35 Stability Data & Dissolution Data of Example 25 at 40° C., 75% RH
- Rat rattus 72 male Wistar rats ( Rat rattus ) (6 per group) were maintained in animal house in a light/dark atmosphere based on a 12 hour cycle having temperature and relative humidity in the range of 22 ⁇ 3° C. and 30-70% respectively. To maintain the appropriate conditions, temperature and relative humidity were recorded three times daily. All animals were acclimatized for a minimum period of five days. Animals were maintained in the test setup for minimum 30 minutes once during the acclimatization period to reduce the stress. Animals were weighed on the day of receipt and observed daily for abnormalities if any. Detailed records of acclimatization were also maintained. Rats were housed 6 per cage in clean, sterilized Polypropylene cages.
- mice were divided as normal control (Group 1), disease control (Group 2), treatment groups with individual components (Group 3, Group 4, Group 5, Group 6 and Group 7 as Lactoferrin, Disodium Guanosine monophosphate (GMP), Guanosine diphosphate (GDP), Guanosine triphosphate (GTP) and Vitamin C respectively), test composition/formulation of the present invention (Group 8 as combination of Lactoferrin Disodium GMP, Group 9 as combination of Lactoferrin GDP, Group 10 as combination of Lactoferrin+GTP, Group 1 as combination of Lactoferrin+Disodium GMP+Vitamin C) and reference standard drug (Group 12).
- Table 1 provides the details of the various groups and treatments conducted in the trial wherein group no. G3 to G12 are treatment groups.
- Group nos. 2 to 12 animals under consideration were administered IDD (3 mg Fe/Kg of diet) for the period of 3 weeks, while group 1 animal received Normal pellet diet (35 mg Fe/Kg of diet).
- Hematocrit % (HCT %) level and serum iron level were determined in each animal. Looking at low increase in hemoglobin. Hematocrit % (HCT %) level and serum iron level, further dietary intervention was continued for additional two (2) weeks.
- Hb level and % Hematocrit level were increased in all treated groups (G3-G12) of animals as compared to disease control group (G2) after treatment for 9 weeks. More importantly, significant increment in Hb level and % Hematocrit level was observed in G8-G11 (Lactoferrin Combination) and G12 compared to disease control group (G2). (See Table 2 and FIG. 1-2 )
- Serum Iron level was increased in all treated groups (G3-G12) of animals as compared to disease control group (G2) after treatment for 9 weeks. More importantly, there was significant increase in the level of serum Iron in case of G8-G11 (Lactoferrin Combination) and G12 (FeSO 4 ) compared to disease control group (2). (See table 2 & FIG. 3 )
- Ferroportin level was decreased in case of disease control group (G2) as compared to normal control group (G1).
- IDD interleukin-6
- hepcidin hepcidin
- hypoferremia hepcidin
- IDD model is the accepted model.
- anaemia was induced by administering IDD (3 mg Fe/Kg of diet) to Group no. 2 to 12 animals for the period of 5 weeks continued up to 14 weeks.
- IDD 3 mg Fe/Kg of diet
- G1 normal control group
- Normal pellet diet 35 mg Fe/Kg of diet
- Hb level and % Hematocrit level were increased in all treated groups (G3-G12) of animals as compared to disease control group (G2) after treatment for 9 weeks. More importantly, it needs to be considered that there was a significant increment (p ⁇ 0.001) in the level of Hb and % Hematocrit in G8-G11 (Lactoferrin Combination) and G12 compared to the disease control group (G2).
- Serum iron level was increased in all treated groups (G3-G12) of animals as compared to disease control group (G2) after treatment for 9 weeks. More importantly, it needs to be considered that there was a significant increase (p ⁇ 0.001) in the level of scrum iron in case of G8-G11 (Lactoferrin combination) and G12 (FeSO 4 ) compared to the disease control group (G2).
- Hepcidin and IL-6 level were significantly increased in case of disease control group (G2) as compared to the normal control group (G1), while it has been noted that ferritin value was marginally increased.
- G8-G11 group (Lactoferrin combination) exhibited the highest effective in treatment of iron deficient anaemia model in rats as summarized in Table 2-3 below. It indicates that Lactoferrin combinations (G8-G11) provide synergistic effect over individual components and plays an important role in iron deficient anaemic rats.
- Group G8-G11 (Lactoferrin combination) exhibit correction of Hepcidin & Inflammatory markers induce Iron deficiency in case of Iron deficient diet induced anaemia model (RAT).
- RAT Iron deficient diet induced anaemia model
- the combination therapy of the present invention is also useful in treating neuro-degenerative disorder as well. While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above.
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PCT/IB2019/051706 WO2019171236A1 (en) | 2018-03-09 | 2019-03-04 | A pharmaceutical composition for anaemia |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114392249A (zh) * | 2022-01-13 | 2022-04-26 | 上海医药集团青岛国风药业股份有限公司 | 一种多糖铁复合物的肠溶微丸及粉末直压片剂 |
WO2023099493A1 (en) * | 2021-12-03 | 2023-06-08 | Dsm Ip Assets B.V. | New delivery system for vitamin c |
CN116530687A (zh) * | 2023-06-03 | 2023-08-04 | 重庆医科大学 | 一种含乳酸亚铁口服溶液及其用途 |
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DE202020101861U1 (de) * | 2020-04-06 | 2020-04-16 | artgerecht GmbH | Eisen-enthaltende Formulierung, ernährungsphysiologische Zusammensetzung, welche diese enthält, und Verwendung derselben |
IT202000012373A1 (it) * | 2020-05-26 | 2021-11-26 | Prosol S P A | Formulazione farmaceutica o di integratore alimentare per l’uso nel trattamento di disturbi dovuti alla carenza di ferro |
IT202000022003A1 (it) * | 2020-09-18 | 2022-03-18 | Difass Int S R L | Composizioni comprendenti un sale minerale per uso orale |
WO2022118274A1 (en) * | 2020-12-03 | 2022-06-09 | Neilos S.r.l. | Compositions for the use in the treatment and/or prevention of iron deficiency conditions or diseases |
WO2024097926A1 (en) * | 2022-11-03 | 2024-05-10 | Nutrition & Biosciences Usa 1, Llc | Oral biologic macromolecule delivery system |
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WO2016073132A1 (en) * | 2014-11-07 | 2016-05-12 | Mjn U.S. Holdings Llc | Nutritional compositions containing a prebiotic and lactoferrin and uses thereof |
WO2018009647A1 (en) * | 2016-07-06 | 2018-01-11 | Building Block Nutritionals, Llc | Nutritional formula |
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US20020022052A1 (en) | 2000-04-06 | 2002-02-21 | Dransfield Charles William | Transdermal delivery system |
CN1218647C (zh) | 2003-04-03 | 2005-09-14 | 石家庄三鹿集团股份有限公司 | 新生婴儿奶粉 |
WO2007022537A2 (en) | 2005-08-19 | 2007-02-22 | Agennix Incorporated | Use of lactoferrin as a chemokine and a chemotactic modulator |
CN102481009A (zh) | 2009-08-13 | 2012-05-30 | 雀巢产品技术援助有限公司 | 包含外源性核苷酸的营养组合物 |
CN106578134A (zh) * | 2016-12-31 | 2017-04-26 | 东北农业大学 | 一种预防感染性腹泻的婴儿配方奶粉 |
CN107549612B (zh) * | 2017-09-12 | 2021-01-12 | 东北农业大学 | 一种提高6-12个月龄婴儿免疫力的营养配方米粉 |
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---|---|---|---|---|
WO2023099493A1 (en) * | 2021-12-03 | 2023-06-08 | Dsm Ip Assets B.V. | New delivery system for vitamin c |
CN114392249A (zh) * | 2022-01-13 | 2022-04-26 | 上海医药集团青岛国风药业股份有限公司 | 一种多糖铁复合物的肠溶微丸及粉末直压片剂 |
CN116530687A (zh) * | 2023-06-03 | 2023-08-04 | 重庆医科大学 | 一种含乳酸亚铁口服溶液及其用途 |
Also Published As
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MY183462A (en) | 2021-02-18 |
MA52154A (fr) | 2020-06-10 |
WO2019171236A1 (en) | 2019-09-12 |
PL3661373T3 (pl) | 2022-10-03 |
PE20201278A1 (es) | 2020-11-24 |
ES2927216T3 (es) | 2022-11-03 |
BR112020018319A2 (pt) | 2020-12-29 |
SG11202008732VA (en) | 2020-10-29 |
CA3073184A1 (en) | 2019-09-12 |
MD3661373T2 (ro) | 2022-11-30 |
MA52154B1 (fr) | 2022-09-30 |
RS63563B1 (sr) | 2022-10-31 |
CO2020010193A2 (es) | 2020-08-31 |
EA202090276A1 (ru) | 2020-11-16 |
HUE059584T2 (hu) | 2022-11-28 |
UA123852C2 (uk) | 2021-06-09 |
EP3661373A1 (en) | 2020-06-10 |
DK3661373T3 (da) | 2022-09-12 |
EP3661373B1 (en) | 2022-06-22 |
AU2019232621B2 (en) | 2020-10-08 |
HRP20221105T1 (hr) | 2022-11-25 |
PH12019550263A1 (en) | 2021-01-11 |
US12016906B2 (en) | 2024-06-25 |
PT3661373T (pt) | 2022-09-22 |
SI3661373T1 (sl) | 2022-10-28 |
CA3073184C (en) | 2021-11-16 |
AU2019232621A1 (en) | 2020-03-12 |
LT3661373T (lt) | 2022-09-26 |
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